Inhaled nitric oxide (NO) is a selective pulmonary vasodilator. Uncontrolled clinical studies have suggested that inhaled NO improves oxygenation in patients with acute lung injury. Although controlled clinical studies evaluating the effectiveness of inhaled NO during acute lung injury have not been done, this agent is being used with increasing frequency in European hospitals. In a canine model of lobar and diffuse bacterial pneumonia which closely simulates the acute lung injury and cardiopulmonary changes which occur in humans with pneumonia, we have shown that short term administration of inhaled NO results in only modest improvements in pulmonary hemodynamics and gas exchange. No animal data is presently available to support the belief that inhaled NO will improve overall outcome during acute lung injury. Inhaled nitric oxide has a number of potential toxicities which should be of great concern in patients presenting with acute lung injury related to pneumonia. Inhaled NO has the capacity to aggravate oxidant lung injury via the formation of peroxynitrite and hydroxyl radical. Such injury might be amplified in patients with inflammatory lung injury on oxygen therapy. NO also, by down-regulating endothelial receptors for leukocyte adhesion and migration may limit important leukocyte host defense function during acute lung injury associated with infection. Studies evaluating the potential toxic long term effects of inhaled nitric oxide during inflammatory lung injury associated with infection have not been conducted. We have now developed the equipment and laboratory techniques necessary for the long term administration and monitoring of inhaled nitric oxide at varying levels of oxygen exposure in small animals. With these resources, we have started preliminary studies evaluating the effects of prolonged inhalation of NO in a rat model of E. coli pneumonia at differing concentrations of oxygen.. These studies are assessing the effects of inhaled NO on survival, oxidative lung injury, extravascular leukocyte recruitment, endothelial and epithelial leukocyte receptor expression, and bacterial clearance. These studies will be continued through the upcoming year. Tissue receptor expression (ICAM-1 and P-selectin) are being conducted on tissues from this study by Dr. Steven Welti from Baylor University.